The p38 mitogen-activated protein kinase (MAPK) is a signaling intermediate downstream of proinflammatory cytokine receptors released following environmental stress. This kinase is known to play an important role in inflammatory and autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. The p38 MAPK family includes four separately encoded members—p38α, p38β, p38γ and p38δ; p38α, p38β and p38δ are expressed in T cells, while p38γ is primarily expressed in skeletal muscle (Jirmanova et al., Blood 118(12):3280-3289, 2011). The p38 kinase is ubiquitously expressed and is activated in all cells by a series of sequential phosphorylation steps that result in dual phosphorylation at threonine 180 and tyrosine 182. However, in T cells, direct stimulation of the T cells through their antigen receptor results in activation of an alternative p38 pathway, leading to phosphorylation of p38α and p38β on tyrosine 323 (Salvador et al., Nat Immunol 6(4):396-402, 2005).
Genetically modified mice that express p38α and p38β containing a tyrosine to phenylalanine substitution at residue 323 (Y323F) have been developed and characterized to better understand the role of the T cell-specific alternative p38 activation pathway in vivo. Due to the phenylalanine substitution, the modified forms of p38α and p38β cannot be phosphorylated at residue 323, which prevents activation of the alternative p38 pathway. The genetically modified mice exhibit a significant reduction in T cell proliferation, proinflammatory cytokine production, as well as reduced susceptibility to animal models of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Studies of these mice established that the alternative p38 activation pathway in T cells plays an important role in T cell activation and the development of autoimmune and inflammatory diseases (Jirmanova et al., Blood 118(12):3280-3289, 2011).
Gadd45 (growth arrest and DNA damage-inducible genes) is a family of proteins that play a role in cell growth regulation, differentiation and apoptosis. In mammalian cells, three different Gadd45 family members have been identified—Gadd45α, Gadd45β and Gadd45γ. Using Gadd45α-deficient mice, prior studies have shown that Gadd45α inhibits the alternative p38 activation pathway, and the absence of Gadd45α results in T cell hyperproliferation and autoimmunity (Salvador et al., Nat Immunol 6(4):396-402, 2005).